Spongiotic Changes Research Articles

Targeting Neuroinflammation by Pharmacologic Downregulation of Inflammatory Pathways Is Neuroprotective in Protein Misfolding Disorders.

Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category of progressive diseases includes, but is not limited to, Alzheimer's disease, Parkinson's disease, and prion diseases. Shared pathogenesis involves the accumulation of misfolded proteins, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, and death. Presently, there are few to no effective treatments to halt the advancement of neurodegenerative diseases. We hypothesized that directly targeting neuroinflammation by downregulating the transcription factor, NF-κB, and the inflammasome protein, NLRP3, would be neuroprotective. To achieve this, we used a cocktail of RNA targeting therapeutics (SB_NI_112) shown to be brain-penetrant, nontoxic, and effective inhibitors of both NF-κB and NLRP3. We utilized a mouse-adapted prion strain as a model for neurodegenerative diseases to assess the aggregation of misfolded proteins, glial inflammation, neuronal loss, cognitive deficits, and lifespan. Prion-diseased mice were treated either intraperitoneally or intranasally with SB_NI_112. Behavioral and cognitive deficits were significantly protected by this combination of NF-κB and NLRP3 downregulators. Treatment reduced glial inflammation, protected against neuronal loss, prevented spongiotic change, rescued cognitive deficits, and significantly lengthened the lifespan of prion-diseased mice. We have identified a nontoxic, systemic pharmacologic that downregulates NF-κB and NLRP3, prevents neuronal death, and slows the progression of neurodegenerative diseases. Though mouse models do not always predict human patient success and the study was limited due to sample size and number of dosing methods utilized, these findings serve as a proof of principle for continued translation of the therapeutic SB_NI_112 for prion disease and other neurodegenerative diseases. Based on the success in a murine prion model, we will continue testing SB_NI_112 in a variety of neurodegenerative disease models, including Alzheimer's disease and Parkinson's disease.

Cutaneous Reactions after COVID-19 Vaccines: Analysis of the Clinical and Histopathological Spectrum-Case Series and Review of the Literature.

(1) Background: Various cutaneous adverse drug reactions (ADRs) are observed with the implementation of mRNA COVID-19 vaccines. To gain insight into the clinicopathologic features, we analyzed the correlation of histological and clinical data in 48 patients with these ADRs. (2) Methods: Single-center retrospective study in patients with ADRs after mRNA COVID-19 vaccination (mRNA-1273 and BNT162b2 vaccines). (3) Results: Distant generalized ADRs prevailed (91%), often appearing clinically as spongiotic dermatitis or maculopapular exanthema. Histopathological analysis revealed spongiotic changes (46%) and dermal superficial perivascular predominantly lymphocytic infiltrates (17%). Eosinophils were found in 66% of biopsies, neutrophils in 29%, and plasma cells only in 8% of biopsies. Most ADRs occurred after the second vaccine dose (44%). Histologically spongiotic changes were associated with clinical features of spongiotic dermatitis in only 50% of patients and maculopapular exanthema in the remaining patients. ADRs represented an aggravation of preexisting skin disease in 23% of patients. ADRs regressed within 28 days or less in 53% of patients and persisted beyond a month in the remaining patients. (4) Conclusions: Our study demonstrates a diverse spectrum of generalized ADRs, revealing correlations between histology and clinical features but also instances of divergence. Interestingly, in about half of our patients, ADRs were self-limited, whereas ADRs extended beyond a month in the other half.

The Anti-Inflammatory and Skin Barrier Function Recovery Effects of Schisandra chinensis in Mice with Atopic Dermatitis.

Background and Objectives: The fruit of Schisandra chinensis (Turcz.) Baill. is widely used medicinally to treat coughs, asthma, exhaustion, eczema, and pruritus in Northeast Asian countries, including Korea, China, and Japan. This study was designed to investigate the effects of S. chinensis on dermatitis in mice with calcipotriol (MC-903)-induced atopic dermatitis (AD), and its effects on skin barrier dysfunction was also investigated. Materials and Methods: The inhibitory effects of an ethanolic extract of S. chinensis (EESC) on skin lesions, water content, water-holding capacity (WHC), histopathological abnormalities, and inflammatory cytokine and chemokine levels were evaluated in mice with AD induced by MC903. Results: Topical EESC ameliorated skin lesions, reduced skin water content, and increased MC903-induced WHC. EESC also prevented MC-903-induced histopathological abnormalities such as epidermal disruption, hyperkeratosis, spongiotic changes, and immune cell infiltration in inflamed tissue. Moreover, topical EESC reduced MC-903-induced levels of pro-inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4, IL-6, IL-8, monocyte chemotactic protein (MCP)-1, and thymic stromal lymphopoietin (TSLP). Furthermore, unlike dexamethasone, EESC did not reduce the spleen/body weight ratio. Conclusions: These results suggest that S. chinensis can be used as an alternative to external corticosteroids and that its anti-inflammatory and skin barrier dysfunction-restoring effects are related to the downregulation of pro-inflammatory cytokines and chemokines, such as TNF-α, IL-4, IL-6, IL-8, and TSLP.

Leukemia Cutis of the Scalp Masquerading as 'Kerion' in a Child.

Dear Editor, Dermatologic manifestations of leukemia can be both specific (leukemia cutis) and nonspecific (leukemids). Leukemia cutis (LC) is defined as neoplastic leukocyte (either lymphoid or myeloid lineage) infiltration into the epidermis, dermis, or subcutaneous tissues.[1] LC may have diverse presentation and may often be misdiagnosed clinically.[2] Histopathology and immunohistochemistry help to clinch the diagnosis of LC. Here, we describe a child who presented with a crusted lesion and patches of alopecia on the scalp mimicking kerion. A 8-year-old male child presented with crusted lesions over the vertex since 3 months. It started as a coin-shaped patch of alopecia, which was treated initially with topical indigenous plant extracts. This led to the formation of a blister, which progressed into a crusted plaque. At the same time, the child developed pain, intermittent fever, and swelling in the neck. A provisional diagnosis of kerion was made by family physician and the child was treated with a course of oral antibiotics and antifungals without any relief. Examination revealed yellowish crusted indurated plaque on the right side of the scalp measuring 8 × 6 cm [Figure 1]. There was another patch of alopecia measuring 3 × 4 cm on the left parietal region. Cervical lymph nodes (submandibular and occipital) were enlarged, tender, and hard in consistency. The child also had swelling of bilateral testicle. Hematological examination revealed anemia (Hb of 6.6g/dL), raised ESR (90 mm/hr), and low total lymphocyte count of 5730 per mL with 18% blast cells. Potassium hydroxide mount from skin scrapings and hair showed no fungal elements. Histopathological examination revealed ulcerated epidermis and dense infiltration with atypical lymphoid cells in the dermis, confirming the diagnosis of leukemia cutis [Figure 2]. Immunohistochemistry analysis of the lymph node biopsy showed that the atypical lymphoid cells were positive for CD45, PAX5, CD99, CD10, bcl6, bcl2, and c-myc and negative for CD 20, CD3, TdT, CD34, Cyclin D1, CD 138, CD 56, and CD117. Marrow aspiration studies revealed 67% blast cells and 20% lymphocytes. Flow cytometry of bone marrow aspirate reported positive B cell markers like CD10, CD19, and CD79a; and negative for CD20. Based on these findings, a diagnosis of Pre-B acute lymphocytic leukemia (ALL) was made.Figure 1: Crusted plaque with peripheral alopecia on the scalpFigure 2: (a) Diffuse infiltration by monotonous population of atypical lymphoid cells in the dermis with loss of skin adnexal structures. Acanthosis of epidermis could be appreciated (H and E, x100). (b) Monomorphic population of atypical lymphoid cells in the dermis showing blastoid morphology defined by high nuclear-cytoplasmic ratio, scant cytoplasm, and irregular clumped chromatin (H and E, x400)Leukemia is the most common malignancy in children; acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the the most common forms of childhood leukemias.[3] LC has been found to be more common in AML than ALL. The most common cutaneous features of LC are papules and nodules followed by plaques; different morphological patterns may coexist in a given patient. It may not be possible to predict the type of underlying malignancy based on the morphology of skin lesions. Two main sites of predilection for LC in children are head and lower extremity.[3] In majority of patients, LC is the initial presenting manifestation of systemic disease. It can also be the manifestation of disease relapse. Rarely, it may precede by several months before the detection of leukemic cells in the peripheral blood (i.e., aleukemic leukemia).[23] Our patient presented initially with alopecia, which gradually progressed to form crusted plaque. Though irritant reaction following the use of plant extract would have led to the formation of a plaque, histopathology did not show significant spongiotic changes. ALL presenting as alopecia is an exceptional phenomenon. Potential pathophysiological mechanisms comprise malignant infiltration of the hair follicle and fibro-collagenous response to infiltration as well as cytokine release.[4] It is very important to perform a thorough general physical examination in a child presenting with alopecia; our case had scrotal swelling and cervical lymphadenopathy, which were hard in consistency. These features prompted us to suspect LC in this case. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Dermatopathology of COVID-19 infection and vaccination.

BackgroundMany peculiar skin changes have been described in relation to both coronavirus disease 2019 (COVID-19) infection and vaccination.ObjectiveThis paper provides an overview of these dermatologic manifestations, focusing on their dermatopathological appearances.ResultsMost COVID-19 patients develop variegated maculopapular eruptions with a combination of histological patterns commonly including keratinocyte apoptosis and eosinophilia. Urticaria-like lesions often show a combination of spongiotic and lichenoid patterns and are more frequent in individuals with severe disease. Vesicular lesions can be disseminated; in some cases, they become pustular and in others show dyskeratosis and a peculiar form of ballooning. Some patients develop vesicular Grover disease on the trunk. Young patients with a strong immunological response can eliminate the virus easily but may develop chilblains as a consequence of the high interferon response. Conversely, older individuals with immunosenescence and a tendency toward hypercoagulability can present livedoid and ischemic areas. Regarding COVID-19 vaccination, hypersensitivity reactions are most frequent, including “COVID-arm.” Nonetheless, a combination of local and systemic cutaneous manifestations (reactogenicity) is commonly seen. Histopathologically, lichenoid and spongiotic changes and a variable number of eosinophils are typical of rashes characterized by papules and plaques. Other dermatological side effects of COVID-19 vaccination include lesions mimicking well-defined dermatoses such as lichen planus or bullous pemphigoid and triggering of collagenous diseases.ConclusionWell-characterized skin manifestations of coronavirus disease 2019 (COVID-19) include chilblains, livedo necrotic lesions, vesicular eruptions, urticarial lesions, and maculopapular eruptions. Hypersensitivity reactions are common after SARS-CoV‑2 mRNA vaccination. Vaccine reactions may also mimic other dermatosis such as bullous pemphigoid or lichen planus, stimulate herpes reactivation, or trigger the development of autoimmune diseases.

PB2125: LYMPHOMATOID PAPULOSIS-LIKE (LYP-LIKE) AFTER BRENTUXIMAB VEDOTIN-CHP (BV-CHP) TREATMENT FOR ALK-NEGATIVE ANAPLASTIC LARGE CELL LYMPHOMA (ALCL)

Background: Lymphomatoid papulosis is an indolent form of CD30 primary cutaneous lymphoproliferative disorder characterized for recurrent crops of self-healing papular nodular lesions. Histological findings may overlap with those in primary cutaneous ALCL so clinical features and evolution determine the appropriate therapeutic approach. Most cases of LyP don’t require any treatment, but PUVA or low-dose oral methotrexate can reduce skin lesions. LyP-like is uncommon after a systemic ALCL. BV-CHP has become the new standard front-line treatment for ALCL in the last years; some aspects of the biological and clinical behavior of the disease with this new therapy are still under research. Aims: NA Methods: NA Results:Patient 1: 45 years female, diagnosed in January/20 with ALK-negative ALCL stage IV-A, IPI 3, involving multiple supra- and infradiaphragmatic lymphadenopathies, spleen, skin, bone and bone marrow. The diagnosis was performed by skin biopsy of an extensive ulcerated mass in the right chest area. FISH showed no rearrangements of DUSP22 and TP63. BV-CHP was started in January/20, achieving PR by PET-CT after 3 cycles. She completed 6 cycles. Four weeks after the last dose of chemotherapy she developed several papular skin lesions in the trunk and extremities. The skin biopsy was reported as ALCL. PET-CT showed metabolic CR at that time. After 3 weeks, the skin lesions spontaneously disappeared and she underwent ASCT conditioned with BEAM in July/20. Two months later, she developed new skin lesions and a new biopsy showed nonspecific findings: perivascular lymphocytic dermatitis with epidermal spongiotic changes. PET-CT showed two enlarged axillary lymphadenopathies with increased activity. A watch and wait strategy was adopted, until September/21 when she relapsed involving multiple lymphadenopathies, bone, spleen and new papulo-necrotic skin lesions. Skin biopsy showed a CD30+ lymphoprolipherative disorder. She received 3 cycles of ESHAP achieving PR, and an haploidentical stem cell transplantation was performed in January/22. Two months after transplant, the patient has no signs of disease and no skin lesions. Patient 2: 62 years male, diagnosed in August/21with systemic ALK-negative ALCL stage IV-B, IPI 3, with supra- and infradiaphragmatic lymphadenopathies and extensive colonic involvement. DUSP22-IRF4 and TP63 rearrangements were assessed, showing no abnormalities. Bone marrow and skin were not affected. He started front-line treatment with BV-CHP in September/21, with metabolic CR in the interim PET-CT after 4 cycles. He completed 6 cycles with good tolerance until late December/21. One month later, he developed papular and papulo-necrotic skin lesions in different evolutionary stages, affecting trunk, extremities and scalp. Skin biopsy was performed, showing a CD30+ lymphoprolipherative disorder. Another PET-CT demonstrated systemic CR. Clinicopathological findings were consistent with lymphomatoid papulosis. The patient underwent an ASCT as consolidation treatment. Currently, the skin lesions have involuted spontaneously. Image:Summary/Conclusion: These two similar cases illustrate an unusual scenario after systemic ALK-negative ALCL, both developed within weeks after frontline chemotherapy with BV-CHP. Diagnosis and therapeutic decisions are challenging. Further experience with this new regimen will reveal whether the addition of BV may play a role in the development of this condition, and whether the clinical course is the same as primary cases of LyP or precedes a relapse of systemic lymphoma.

Is “Localized juvenile spongiotic gingival hyperplasia” an appropriate term? Insights based on a case series and literature review

<h3>Introduction</h3> Localized juvenile spongiotic gingival hyperplasia (LJSGH) is an entity presenting as reddish gingival enlargements microscopically exhibiting spongiotic non-keratinized epithelium with inflammatory exocytosis. To this date, various terms have been proposed, but, arguably, none of them has accurately described the clinicopatho- logic features and origin of these lesions. Additionally, insufficient emphasis has been given on their microscopic characteristics. <h3>Materials and methods</h3> Lesions with a diagnosis of LJSGH, established by histopathologic examination and CK19 immunoreactivity (in equivocal cases), were retrieved. The patients' demographic and clinical characteristics were collected. Additionally, microscopic features were assessed including the extent of spongiotic changes and epithelial surface morphology (flat vs. papillary). A review of the pertinent English language literature was conducted. <h3>Results</h3> Eighteen patients with a total of 21 biopsied lesions were identified, exhibiting a mean age of 19.2 years (range: 8-57) and a slight female predilection (10:8). The most common site of involvement was the facial maxillary gingiva (17 lesions), while 4 patients exhibited multifocal lesions. Microscopically, 16 lesions showed prominent epithelial spongiosis, while flat morphology was more common than papillary (13:8). The literature review disclosed 203 cases including those presented herein. A mean age of 14.7 years was recorded, with almost equal gender distribution (103:100, F: M), while the anterior maxilla was affected more commonly (>80% of lesions). Eighteen patients displayed multifocal lesions. <h3>Conclusions</h3> Since almost 10% of LJSGHs are multifocal, the word "localized" could be omitted. Additionally, pa- tients over 50 may be involved, hence the term "juvenile" may be also misleading. "Hyperplasia", a histopathologic term referring to increases in number of cells, does not always characterize these lesions that could occasionally display epithelial atrophy (especially the flat subtype). Finally, the entity's odontogenic origin, as supported by the resemblance to the junctional epithelium and the immunophenotypic features, may need to be emphasized.

Dictamnus dasycarpus Turcz., root bark alleviates oxazolone-induced atopy-like dermatitis in mice

Background: Dictamnus dasycarpus Turcz., is one of the most frequently used herbal medicine to treat dermatosis associated with psoriasis, pruritus, scabies, and eczema. Objective: We investigated the anti-inflammatory effects of D. dasycarpus extract (DDE) using a mouse model with atopic dermatitis (AD)-like dermatitis. Materials and Methods: The therapeutic effects of DDE on skin lesion, tone of color, and inhibitory effects on histopathological changes and cytokine production in skin tissues were assessed in mice with AD-like dermatitis induced by oxazolone. Results: Topical application of DDE alleviated skin lesions such as erythema, scaling and excoriations, and ameliorated erythema and the melanin index. In addition, DDE effectively prevented skin enlargement induced by oxazolone, while also preventing epidermal hyperplasia, spongiotic change, and hyperkeratosis and reducing the production of tumor necrosis factor-alpha and interleukin (IL)-4 and IL-5 in inflamed tissues. Finally, DDE did not affect changes in body weight and spleen–body weight ratio relative to dexamethasone. Conclusion: These results indicate that D. dasycarpus can be used as a topical agent for inflammatory skin diseases with relative safety. Abbreviation used: HM: Herbal medicine; DNFB: Dinitrofluorobenzene, ICAM-1: Intercellular adhesion molecule-1, AD: Atopic dermatitis, DDE: Dictamnus dasycarpus extract, AOO: Vehicle composed of acetone and olive oil, DEX: Dexamethasone, CBA: Cytometric bead array.

Histopathologic Features in Animal Model of Atopic Dermatitis Induced by Topical Application of Oxazolone

Animal models of atopic dermatitis (AD) are widely used to investigate therapeutic effects of candidates for AD. However, the characteristics of each model are not fully understood. This study was designed to compare the animal models of dermatitis induced by dinitrofluorobenzene (DNFB) and oxazolone (Ox). We investigated the effects of DNFB and Ox on skin thicknesses and weights as well as skin lesions associated with AD such as scale, crust and erythematous eruption, and histopathological changes such as hyperkeratosis, dermal and epidermal hyperplasia and immune cell infiltration in inflamed tissues. Multiple application of 0.5% Ox onto the skin increased skin thickness and weight compared to those of DNFB treated mice, as well as those of normal mice. In addition, topical application of DNFB induced marked scale, crust and erythematous eruption, while Ox induced erythematous eruption and mild scale and crust. Histopathological examination revealed that 0.5% Ox induced marked hyperplasia in the dermis and epidermis, large vesicles, spongiotic changes, mild hyperkeratosis and immune cell infiltration in balb/c mice. These data suggest that multiple applications of Ox can induce chronic AD like dermatitis in balb/c mice.

Decoction of Dictamnus Dasycarpus Turcz. Root Bark Ameliorates Skin Lesions and Inhibits Inflammatory Reactions in Mice with Contact Dermatitis.

Background:The root bark of Dictamnus dasycarpus Turcz. (Dictamni Radicis Cortex) has been widely used to treat skin diseases in Korea, and its anti-inflammatory efficacies were recently reported.Objective:The paper aims to investigate the inhibitory effects of decoction of Dictamni Radicis Cortex (DDRC) in mice with contact dermatitis (CD).Materials and Methods:We investigated the effects of DDRC on skin lesion characteristics such as crust, scales, incrustation and petechiae, the erythema and melanin indexes, skin thickness, histopathologic changes, and cytokine production in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced CD mice.Results:Topical application of DDRC ameliorated crust, scales, incrustation, and induced by DNFB. In addition, DDRC lowered the erythema index significantly (P < 0.05). DDRC effectively inhibited enlargement of skin thickness (P < 0.05). Histopathologic observation showed that DDRC inhibited epidermal hyperplasia, hyperkeratosis, and spongiotic changes. Finally, DDRC decreased production levels of IFN-γ, TNF-α and IL-6 induced by repeated application of DNFB (P < 0.05).Conclusion:These data suggest that DDRC can be used in the treatment of inflammatory skin diseases including CD. Moreover, these results are closely related to the decreasing production of TNF-α IFN-γ and IL-6 in inflamed tissues.SUMMARY DDRC ameliorated skin lesions such as crust, scales, incrustation and petechiae, and lowered erythema index on skin surface in CD miceDDRC inhibited enlargement of dorsal skin and prevented epidermal hyperplasia, hyperkeratosis, and spongiotic changes in inflamed tissuesDDRC reduced the levels of TNF-α, IFN-γ, and IL-6 in inflamed tissues of CD miceDDRC did not affect spleen/body weight ratio in CD mice. Abbreviations used: DDRC: decoction of Dictamni Radicis Cortex, CD: contact dermatitis, DNFB: 1-fluoro-2,4-dinitrofluorobenzene, AOO: acetone and olive oil, DEX: dexamethasone, CBA: cytometric bead array

Background data on NOD/Shi-scid IL-2Rγnull mice (NOG mice).

To obtain background data of NOD/Shi-scid IL-2Rγnull (NOG) mice, severely immunedeficient mice, a total of 120 animals were examined at 7, 26 and 52 weeks-old (20 mice/sex/group). The survival rate at 52 weeks-old was 95% (19/20) in both sexes. Clinically, circling behavior in one direction along the cage wall was observed in males after 8 weeks and females after 47 weeks-old, and hunchback position was found in males after 32 weeks-old. Hematologically, lymphocyte count markedly decreased at all ages, while white blood cell count increased in several mice at 52 weeks-old. Blood chemistry results revealed high values of aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase in some females at 26 weeks-old, without any related histological change. Histologically, lymphoid hypoplasia characterized by severe lymphocyte depletion with poorly developed tissue architectures was observed. In addition, spongiotic change in the nerve tissue was observed in both sexes at 7 and 26 weeks-old, and intracytoplasmic materials known as tubular aggregates in the skeletal muscles were found in males terminated at 26 and 52 weeks-old and in females at 52 weeks-old. Malignant lymphoma was found in one female euthanized at 20 weeks-old. Further, small intestinal adenoma, hepatocellular adenoma, leukemia, cerebral lipomatous hamartoma, Harderian gland adenoma and uterine polyp were also observed, and their incidences were low except for that of uterine polyp. This study provided detailed background data on NOG mice up to 52 weeks-old and provided information on appropriate use of NOG mice in the various research fields.

Pathological background of subcortical hyperintensities on diffusion-weighted images in a case of neuronal intranuclear inclusion disease

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with eosinophilic intranuclear inclusion bodies. The variable symptoms of NIID increase the difficulty in an antemortem diagnosis. NIID shows leukoencephalopathy on brain magnetic resonance imaging MRI, but the significance of the radiological findings have not been clarified. We examined an autopsied case of NIID with subcortical linear hyperintensities on diffusion weighted imaging (DWI) and leukoencephalopathy on fluid attenuation inversion recovery (FLAIR) imaging. Semiquantitative analysis was performed by merging coronal sections of DWI and identical hematoxylin-eosin (H & E) stained brain specimens. The severity of spongiotic changes, the common pathological findings of NIID, were quantified and compared with MRI lesions classified by DWI signals. The white matter showed diffuse myelin pallor, and multiple focal spongiotic changes were present in the subcortical white matter proximal to the U-fibers. Spongiotic changes were restricted in the lesions with subcortical linear DWI high signals. Subcortical DWI high signals in NIID strongly correlate with pathological spongiotic changes of NIID. Subcortical spongiotic changes may be a characteristic finding of NIID. .

Miliary tuberculosis characterised by lipomembranous fat necrosis

Figure: Miliary tuberculosis (A) Lipomembranous fat necrosis at 200× magnifi cation. (B) Ulceration and poor healing several months after the initial cellulitis-like presentation. A 29-year-old Dominican woman on chronic prednisone therapy because of a history of Lofgren’s syndrome presented with recurrent fevers, pleuritic chest pain, and joint swelling. Examination revealed diff use synovitis and notable swelling and erythema of the right elbow. MRI of her right elbow showed diff use signal intensity in the subcutaneous fat and superfi cial myofascial planes consistent with cellulitis. A chest CT scan showed several small lung nodules. After mild improvement with intravenous antibiotics, she was discharged on oral antibiotics. She returned 2 weeks later with high fever, nausea, vomiting, and no improvement of her elbow. Despite broad-spectrum intravenous antibiotics, her right elbow swelling did not improve. A skin punch biopsy revealed epidermis with subacute spongiotic changes overlying oedematous and sclerotic dermis. The deep dermis and subcutis were diff usely necrotic and lined at the superfi cial edge by xanthogranulomatous infi ltrate consistent with lipomembranous fat necrosis (fi gure, A). No infectious organisms were initially identifi ed by stain or culture. Included in her extensive infectious work-up was a T-SPOT tuberculosis test, which returned a positive result. Subsequent induced sputum showed acid-fast bacilli that were identifi ed as Mycobacterium tuberculosis. The patient was started on a four-drug regimen for treatment (ethambutol 800 mg per day, isoniazid 300 mg per day, moxifl oxacin 400 mg per day, and pyrazinamide 1500 mg per day). After 3 weeks, right elbow skin biopsy acid-fast cultures became positive for M tuberculosis and a diagnosis of miliary tuberculosis was made. The patient’s elbow ultimately ulcerated and healed slowly within several months (fi gure, B), and the patient was seen to have the additional cutaneous manifestation of tuberculous gummas on her right forearm and in several other locations on her body. The patient completed 9 months of antimycobacterial therapy with clinical improvement and resolution of her cutaneous lesions. At 20-month follow-up after completion of therapy, the patient remains without evidence of active disease. Cutaneous involvement in miliary tuberculosis is rare, but is more common in immunocompromised patients. Rarely, this can result in a cellulitis-like appearance, as was seen at fi rst presentation in this patient. Unlike previous reports, the epidermal changes in this case were associated with lipomembranous fat necrosis. Interestingly, lipomembranous fat necrosis is regarded as a non-specifi c reaction pattern of adipose tissue to injury typically from an impaired blood supply. It can occur in a range of conditions, including vascular disorders, connective tissue diseases, and infl ammatory panniculitis. It has been reported in association with atypical mycobacteria, but an association with M tuberculosis has not been previously described. Although the pathogenic mechanisms that lead to lipo membranous fat necrosis remain unknown, miliary tuberculosis should be added to the list of related disorders.

Eccrine Chromhidrosis Resembling Clinical Features of Pompholyx with Bile-Like Greenish Pigmentation on the Right Palm and Soles.

Dear Editor: Chromhidrosis is a rare condition characterized by secretion of colored sweat from the eccrine or apocrine glands. Not only is this condition epidemiologically rare, but also its mimicry of eczematous clinical features may lead to misdiagnosis. A 55-year-old man was examined for abnormal pigmentation on right palm and soles, which lasted a week. He was a local farmer in an apple orchard and he had diabetes, alcoholic liver cirrhosis, and hepatic regenerative nodules as underlying diseases. He was hospitalized due to longstanding diarrhea and fever. On clinical examination, yellow and green papules were observed on his right palm and soles (Fig. 1) and levels of total (19.3 mg/dl) and direct (13.8 mg/dl) bilirubin were elevated. Histological findings revealed hyperkeratosis, diffuse acanthosis, and subcorneal vesicles in the epidermis (Fig. 2A). Homogenous eosinophilic materials were observed surrounding the vesicles and both the number and size of eccrine glands were increased (Fig. 2A, inset). Hence, the patient was diagnosed with eccrine chromhidrosis and treated with emollient. After three weeks, abnormal pigmentation was almost resolved, levels of total (2.18 mg/dl, normal range: 0.3~1.9 mg/dl) and direct (0.71 mg/dl, normal range: 0~0.3 mg/dl) bilirubin were lower and body temperature had decreased (Fig. 2B). Fig. 1 (A) Multiple yellow and green papules without symptoms on the right hand and (B) soles of both feet. Upper inset: yellow and green pigmentation on the sole. Fig. 2 (A) Upon histopathological examination of a yellow papule, the epidermis showed hyperkeratosis, diffuse acanthosis, and subcorneal vesicles (H&E, ×40). An increased number and size of eccrine glands (lower inset, ×200). Homogenous ... Green pigmentation on the palms and soles in patients with hyperbilirubinemia is a rare condition1. While our case presented with eczematous lesions on the right palm and soles (where sweat glands are most abundant), the patient's clinical features resembled pompholyx, a primarily spongiotic dermatitis2,3. However, the yellow-green pigmentation in our case appeared to be bile-filled vesicles, which could not be explained by spongiotic changes alone. Two weeks of high fever led to increased sweating and high concentrations of bile components in the sweat may have acted as a sensitizer and induced eczematous lesions, exacerbating the inflammatory spongiosis. Eccrine chromhidrosis is a rare condition in which water-soluble pigments from certain dyes or drugs are excreted via the eccrine sweat glands-in our case, the bile components. It may be caused by chromogenic bacterial or fungal contamination or by extrinsic chemicals on the surface of the skin, which react with eccrine secretions and produce the color transformation. However, results of fungal and pseudomonal tests in this case were negative. Kanzaki and Tsuda4 reported two cases of eccrine chromhidrosis with liver disease. In hepatocytes associated with liver disease, bile may become pigmented with brown color; however, no bile pigmentation was observed in this case. The bile pigment may have been washed out during histological fixation if it was located within the spaces of the eccrine ducts and vesicles, and not in the cellular spaces2. Possible pathomechanisms of three essential factors that could contribute towards the development of pigmentation: (1) increased plasma level of water-soluble direct bilirubin, (2) high fever with sweating, and (3) a thick horny layer. The green color is attributable to the switch from brown-colored bilirubin to green-colored biliverdin by oxidative processes5. We report a case of eccrine chromhidrosis resembling the clinical features of pompholyx with explanation of probable pathomechanism.

'Clues' for the histological diagnosis of tinea: how reliable are they?

'Clues' for the histological diagnosis of tinea: how reliable are they?

Photosensitive spongiotic/lichenoid eruption of micropapules and plaques: A morphologically distinct entity

A distinct morphological pattern of photodermatosis has been observed with shiny skin colored to hypopigmented tiny papules, discrete or coalescing to form plaques. To study the clinico-pathological features of patients presenting with these lesions. A total of 72 patients were recruited. Clinical examination and skin biopsy was carried out to evaluate the morphological patterns and the histopathological features. In all patients, tiny discrete to coalescent papules were observed on sun-exposed sites but usually sparing the face. The condition occurred more commonly in women. Three specific histopathological patterns were observed : spongiotic (43.7%), lichenoid (22.5%), psoriasiform (18.7%) and also perivascular pattern in 5%. Photosensitive lichenoid eruption is a morphologically distinct photodermatoses that is commonly seen in Indian patients with pathological features showing mostly spongiotic changes and in some cases lichenoid changes.

Type 2 Helper T-Cell Cytokines Induce Morphologic and Molecular Characteristics of Atopic Dermatitis in Human Skin Equivalent

Both the immune system and the epidermis likely have an important role in the pathogenesis of atopic dermatitis (AD). The objective of the present study was to develop a human skin equivalent model exhibiting morphologic and molecular characteristics of AD in a controlled manner. Skin equivalents generated from normal adult human keratinocytes were stimulated with type 2 T-helper cell (Th2) cytokines IL-4 and IL-13, and morphologic features and gene expression of the epidermis were studied. Th2 cytokines induced intercellular edema similar to spongiotic changes observed in lesional AD as assessed at histopathologic analysis and electron microscopy. Furthermore, genes known to be specifically expressed in epidermis of patients with AD such as CAII and NELL2 were induced. In contrast, expression of psoriasis-associated genes such as elafin and hBD2 was not changed. Th2 cytokines caused DNA fragmentation in the keratinocytes, which could be inhibited by the caspase inhibitor Z-VAD, which suggests that apoptosis was induced. In addition, up-regulation of the death receptor Fas was observed in keratinocytes after Th2 cytokine stimulation. IL-4 and IL-13 induced phosphorylation of the signaling molecule STAT6. It was concluded that the skin equivalent model described herein may be useful in investigation of the epidermal aspects of AD and for study of drugs that act at the level of keratinocyte biology.

Isolated itching of external auditory canal: clinicopathological study with immunohistochemical determination of antimicrobial peptides

This study aimed to demonstrate the histological and immunohistological features of skin biopsy specimens from patients complaining of isolated itching of the external auditory canal. A prospective, case-control study was performed of 24 patients undergoing evaluation for contact dermatitis of the external auditory canal, and 24 controls. Skin biopsies were examined histologically by a single, blinded dermatopathologist, using light microscopy, to determine histopathological characteristics. The immunohistological presence of the antimicrobial peptides human β-defensin-3 and LL-37 cathelicidin was also assessed. Findings for patients and controls were compared. There was a statistically significant difference in the degree of inflammation, comparing patients and controls (p < 0.05). There was no significant difference in the presence of spongiotic changes, comparing patients and controls (p > 0.05). Furthermore, the patients' skin biopsies did not show pronounced expression of human β-defensin-3 or LL-37 cathelicidin. Histological and immunohistological examination of skin biopsies from cases of isolated itching of the external auditory canal did not support a diagnosis of dermatitis.

CD56highCD16−CD62L− NK Cells Accumulate in Allergic Contact Dermatitis and Contribute to the Expression of Allergic Responses

Allergic contact dermatitis is a common disease caused by an exaggerated T cell-mediated immune response to skin-applied haptens. We show in this study that NK cells affect skin immune responses to haptens by releasing type 1 cytokines and inducing keratinocytes apoptosis. Immunohistochemical stainings demonstrated that NK lymphocytes constitute approximately 10% of the inflammatory infiltrate mostly distributed in the superficial dermis and in the epidermis at the site of intense spongiotic changes. More than 90% of NK cells isolated from allergic contact dermatitis skin showed a CD3-CD56(high)CD16- phenotype by FACS analysis. In addition, they uniformly expressed NKG2A, intermediate to high levels of perforin, and the activating receptors, NKG2D, NKp44, and NKp46, but lacked NKp30 and killer Ig-related receptors. Skin NK lymphocytes displayed a CXCR3+CCR6+CCR5+ chemokine receptor asset for homing into inflamed skin, but not CD62L and CCR7 for lymph node homing. When NK cells from nickel-allergic donors were exposed in vitro to the metal, they failed to proliferate, to upregulate CD69, and to release IFN-gamma, thus indicating that NK lymphocytes do not exhibit memory-like properties to haptens. However, IL-2 released by hapten-driven T lymphocytes rapidly induced the release of IFN-gamma by NK cells and promoted the NK-mediated apoptosis of autologous keratinocytes in a hapten-independent manner. Our findings underline the importance of the interaction between innate and adaptive immune mechanisms for amplification of skin allergic responses to haptens and full expression of allergic contact dermatitis.

Preferential involvement of the basolateral limbic circuit in an amyotrophic lateral sclerosis patient

Sirs, In this report, we describe a patient of amyotrophic lateral sclerosis (ALS) with dementia (ALSD) unusually presenting with personality changes or social misconduct which led to an initial diagnosis of Pick’s disease (PiD) 5 years prior to the appearance of motor neuron signs. Accentuated degeneration in the basolateral limbic circuit plausibly explains these initial manifestations [1]. A 46-year-old woman presented with progressive social misconduct, auditory and persecutory hallucination and abnormal sexual behaviors, which led to an initial clinical diagnosis of PiD or schizophrenia by a group of psychiatrists several years later. After progressive worsening of these symptoms, she became mute. She then gradually exhibited weakness and atrophy of the upper limbs after age 51. Needle electromyography showed lower motor neuron involvement and she was diagnosed as suspected ALS. Computed tomography of the brain demonstrated moderate atrophy in the fronto-temporal lobes. Single photon emission computed tomography showed a decreased uptake of the tracer not only in these atrophic areas but also in the bilateral basalganglia and thalami. She died of respiratory failure at age 53. The brain weighed 1160 g and macroscopically showed moderate atrophy of the fronto-temporal cortices, hypopigmentation of the substantia nigra and mild atrophy of the spinal cord and anterior roots. Microscopic investigation demonstrated degeneration of lower motor neurons with Bunina bodies. Upper motor neurons were mostly preserved. Spongiotic changes in layers II-III of the fronto-temporal cortices was accentuated in the orbital gyrus, mediodorsal-ventral temporal tip, and entorhinal region (Fig. 1a and b). Neuronal loss and gliosis were mild to moderate in the medio-dorsal (MD) nucleus of the thalamus (Fig. 1c), caudate nucleus and accumbens. Involvement of the amygdala was moderate to severe. Cytoplasmic inclusions (CI) in neurons immunopositive for ubiquitin and TDP-43 were present in the dentate granular cells, superficial small neurons in the fronto-temporal cortices, striatum, amygdala, and MD nucleus of the thalamus (Fig. 1d). The ubiquitin-positive CI in the striatum exhibited eosinophilia with H&E staining which had been thought to be invisible by H&E. There were few neurofibrillary tangles and amyloid senile plaques. Pick bodies were absent. Presence of Bunina bodies and cortical lesions with the CI confirmed ALSD. Although extramotor involvement in ALSD could be variable, this case is characterized by a unique distribution of the lesions, found in the orbital gyrus, temporal pole, amygdala, and MD nucleus of the thalamus. These structures are collectively grouped as basolateral limbic circuit [1] based on their anatomical